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  3. A ROS-mediated oxidation-O-GlcNAcylation cascade governs ferroptosis

A ROS-mediated oxidation-O-GlcNAcylation cascade governs ferroptosis

  • Nat Cell Biol. 2025 Aug;27(8):1288-1300. doi: 10.1038/s41556-025-01722-w.
Hemeng Zhang # 1 2,  Jialin Ma # 3,  Chunyan Hou 2,  Xuehui Luo 1,  Shiya Zhu 2,  Yihan Peng 2,  Changmin Peng 4,  Ping Li 2 3,  Heng Meng 2,  Yuqi Xia 2,  Zhinuo Jiang 5,  Susree Modepalli 2,  Anju Duttargi 2,  Gary M Kupfer 2,  Mengjiao Cai 1,  Heng Zhang 6,  Junfeng Ma 7,  Juanjuan Li 8,  Suxia Han 9,  Huadong Pei 10
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 2 Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA.
  • 3 Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China.
  • 4 GW Cancer Center, Department of Biochemistry & Molecular Medicine, George Washington University, Washington DC, USA.
  • 5 Flow Cytometry and Cell Sorting Center, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA.
  • 6 Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China. tracyheng0719@163.com.
  • 7 Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA. junfeng.ma@georgetown.edu.
  • 8 Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China. juanjuan.li@whu.edu.cn.
  • 9 Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. shan87@xjtu.edu.cn.
  • 10 Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA. huadong.pei@georgetown.edu.
  • # Contributed equally.
PMID: 40681752 DOI: 10.1038/s41556-025-01722-w
Abstract

Reactive Oxygen Species (ROS) play a crucial role in lipid peroxidation and the initiation of Ferroptosis, markedly affecting chemotherapeutic drug resistance. However, the mechanisms by which ROS function and are sensed remain poorly understood. In this study, we identified O-GlcNAc transferase (OGT), a key enzyme in protein O-GlcNAcylation, as a sensor for ROS during Ferroptosis. The ROS-induced oxidation of OGT at C845 in its catalytic domain activates the enzyme. Once activated, OGT O-GlcNAcylates FOXK2, enhancing its interaction with importin α, which facilitates FOXK2's nuclear translocation and binding to the SLC7A11 promoter region. This, in turn, boosts SLC7A11 transcription, thereby inhibiting Ferroptosis. The elevated OGT-FOXK2-SLC7A11 axis contributes to tumorigenesis and resistance to chemoradiotherapy in hepatocellular carcinoma (HCC). Our findings elucidate a ROS-induced oxidation-O-GlcNAcylation cascade that integrates ROS signalling, O-GlcNAcylation, FOXK2-mediated SLC7A11 transcription and resistance to both Ferroptosis and chemoradiotherapy.

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